| Autor: |
Sabharwal NC; Department of Chemistry and Biochemistry, Swarthmore College, Swarthmore, PA 19081, USA. navin.sabharwal.424@gmail.com.; Lerner College of Medicine, Cleveland Clinic, Cleveland, OH 44195, USA. navin.sabharwal.424@gmail.com., Chen J; Department of Chemistry and Biochemistry, Swarthmore College, Swarthmore, PA 19081, USA. ymchen.017@gmail.com.; School of Dental Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. ymchen.017@gmail.com., Lee JHJ; Department of Chemistry and Biochemistry, Swarthmore College, Swarthmore, PA 19081, USA. jlee2143@gmail.com.; College of Dentistry, New York University, New York, NY 10010, USA. jlee2143@gmail.com., Gangemi CMA; Department of Chemical Science, University of Catania, 95125 Catania, Italy. gangemichiara@unict.it., D'Urso A; Department of Chemical Science, University of Catania, 95125 Catania, Italy. adurso@unict.it., Yatsunyk LA; Department of Chemistry and Biochemistry, Swarthmore College, Swarthmore, PA 19081, USA. lyatsun1@swarthmore.edu. |
| Abstrakt: |
G-rich DNA sequences have the potential to fold into non-canonical G-Quadruplex (GQ) structures implicated in aging and human diseases, notably cancers. Because stabilization of GQs at telomeres and oncogene promoters may prevent cancer, there is an interest in developing small molecules that selectively target GQs. Herein, we investigate the interactions of meso -tetrakis-(4-carboxysperminephenyl)porphyrin (TCPPSpm4) and its Zn(II) derivative (ZnTCPPSpm4) with human telomeric DNA (Tel22) via UV-Vis, circular dichroism (CD), and fluorescence spectroscopies, resonance light scattering (RLS), and fluorescence resonance energy transfer (FRET) assays. UV-Vis titrations reveal binding constants of 4.7 × 10⁶ and 1.4 × 10⁷ M -1 and binding stoichiometry of 2⁻4:1 and 10⁻12:1 for TCPPSpm4 and ZnTCPPSpm4, respectively. High stoichiometry is supported by the Job plot data, CD titrations, and RLS data. FRET melting indicates that TCPPSpm4 stabilizes Tel22 by 36 ± 2 °C at 7.5 eq., and that ZnTCPPSpm4 stabilizes Tel22 by 33 ± 2 °C at ~20 eq.; at least 8 eq. of ZnTCPPSpm4 are required to achieve significant stabilization of Tel22, in agreement with its high binding stoichiometry. FRET competition studies show that both porphyrins are mildly selective for human telomeric GQ vs duplex DNA. Spectroscopic studies, combined, point to end-stacking and porphyrin self-association as major binding modes. This work advances our understanding of ligand interactions with GQ DNA. |
